First-line therapy with pembrolizumab is associated with frequent and durable responses in patients with advanced Merkel cell carcinoma (MCC), according to a study presented at the annual meeting of the American Association for Cancer Research.

The objective response rate wad 56% among 25 patients with MCC who had received at least one dose of pembrolizumab in a phase II study, Dr. Paul Nghiem said at a press conference during the meeting.

This rare but aggressive skin cancer has been notoriously hard to treat with typical chemotherapy of platinum compounds and etoposide, with half of tumors progressing by 3 months and 90% progressing by 10 months. MCC is about three times more likely to kill a patient compared with melanoma.

Given that about 40% of the 2,000 cases per year develop advanced disease, pembrolizumab has the potential to be an advance over chemotherapy although at this point no therapy is approved by the Food and Drug Administration for MCC advanced disease. The disease may be caused by ultraviolet light exposure in older individuals or with immune suppression. In about 80% of cases, Merkel cell polyomavirus (MCPyV) is present, but the virus is ubiquitous in the environment, with widespread exposure in the population without ill effects for most people.

Pembrolizumab acts to block the interaction of PD-1 on tumor-specific or MCPyV-specific T cells with its ligand, PD-L1, on tumor cells or antigen-presenting cells, thus allowing the T cells to recognize the tumors and enhance tumor cell killing.

In a phase II multicenter, single-arm, open-label trial, patients with unresectable or metastatic disease who had never before received any systemic therapy received pembrolizumab 2 mg/kg IV every 3 weeks for up to 2 years. Tumor evaluations were done every 9 or 12 weeks with a median follow-up of 7.6 months.

Of the 25 patients who had received at least one dose and had at least one radiological assessment, there was an objective response rate of 56% (14/25), including 4 complete, 10 partial, and 1 unconfirmed partial response. One patient had stable disease, and nine had progressive disease.

“By the first scan at 3 months most patients have found where they were going to go,” said Dr. Nghiem, professor of medicine in dermatology at the University of Washington, Seattle. “Several had failed early, but by the time of the first scan at 3 months there were often very profound and complete responses, and a lot of the partial responses just remain very steady over time.”

With the caveat that this was not a randomized trial, he said the progression-free survival (PFS) among responders was 67% at 6 months and the median PFS was 9 months, compared to a historical median overall survival with chemotherapy of 9.5 months after metastatic diagnosis. Among responders, 86% continue to have excellent disease control more than 6 months after starting therapy.

Objective responses in this small study appeared to be associated with positive viral status of the tumors. Among patients with virus-positive tumors, 62% (10/16) had objective responses vs. 44% (4/9) in whom the tumors were virus negative. “That was not a statistically significant difference … but maybe suggests, like head and neck [cancers], there may be a better story there for virus positive,” Dr. Nghiem said. PD-L1 expression in the tumors did not predict responses.

In response to a question during the news conference about the high response rate compared to responses to therapy of most other solid tumors, Dr. Nghiem pointed out, “Historically, this has been a very immune-associated cancer … If you had CD8 T cells infiltrating into this cancer at any reasonable number, among 300 patients not one died of the disease.” Unleashing the immune system in this trial through PD-1 blockade may therefore help to explain the good outcomes.

Adverse events were managed with corticosteroid treatment and discontinuing the drug. Two patients who had severe drug-related toxicities improved after steroids and stopping the drug. But, nonetheless, they have ongoing antitumor responses several months after stopping pembrolizumab.

The investigators are currently expanding the trial and recruiting more patients.

The study was simultaneously published online in the New England Journal of Medicine (2016 April 19. doi: 10.1056/NEJMoa1603702 ).

The study was supported in part by Merck. Dr. Nghiem is a consultant to EMD Serono and has grant/research support from Bristol-Myers Squibb.


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